European Patent Application Publication No. 29265 discloses that azetidine-3-carboxylic acid and related compounds are useful as plant hybridizing agents, based on their ability to produce male sterility in plants. Azetidine-3-carboxylic acid can be prepared from 1-benzhydrylazetidin-3-ol, which is prepared by the reaction of epichlorohydrin with benzhydrylamine: A. G. Anderson, Jr. and R. Lok, Journal of Organic Chemistry, 1972, volume 37, pages 3953-5. According to that article, the alcohol is converted to the mesylate ester, which is converted to the nitrile, which is converted to the carboxy acid, then the protective benzhydryl moiety is removed by hydrogenation.
However, the introduction of a benzhydryl group is very inconvenient for an economically practicable synthesis route, since the size of that group greatly increases the bulk of material to be processed, only to be removed once its protective function is no longer required. It would be economically very desirable to use a protective group less bulky than the benzhydryl group, and applicants have found that azetidine-3-carboxylic acid can be prepared by heating an aqueous mixture of N-benzyl-3-cyanoazetidine and barium hydroxide and then treating the mixture with carbon dioxide, to form N-benzylazetidine-3-carboxylic acid, then removing the protective benzyl moiety by hydrogenation.
However, preparation of azetidine-3-carboxylic acid from N-benzyl-3-cyano azetidine involves practical difficulties of compound separation/extraction as a consequence of its high water solubility--which problems do not occur when using the benzhydryl analogue, since the analogue is essentially insoluble in water and therefore is readily freed from inorganic contaminants/by-products. Applicants have therefore sought a practically convenient route for hydrolyzing N-benzyl-3-cyanoazetidine to N-benzyl-3-carboxylic acid and have surprisingly discovered that conversion via the methyl ester affords a unique combination of process advantages, namely effective separation of the organic ester product from an aqueous reaction medium and the inorganic impurities contained therein, and also the ability of the methyl ester to undergo hydrolysis with hot water.